Frailty and Effects of Semaglutide in Obesity-Related HFpEF: Findings From the STEP-HFpEF Program
- PMID: 40956259
- DOI: 10.1016/j.jchf.2025.102610
Frailty and Effects of Semaglutide in Obesity-Related HFpEF: Findings From the STEP-HFpEF Program
Abstract
Background: Frailty is common in heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) program, semaglutide improved heart failure (HF) symptoms and physical limitations and reduced body weight (BW) in participants with obesity-related HFpEF. Whether the efficacy and safety of semaglutide vary by frailty and the effects of semaglutide on frailty are unknown.
Objectives: This study sought to evaluate the efficacy of semaglutide in participants with obesity-related HFpEF according to frailty status at baseline.
Methods: The authors performed a prespecified, pooled, participant-level analysis of the STEP-HFpEF program that included participants with obesity-related HFpEF. Participants were randomized to once-weekly semaglutide, 2.4 mg, or placebo for 52 weeks. Dual primary endpoints were changes in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and BW. Frailty was estimated using a cumulative deficit-derived frailty index comprising 34 variables across multiple domains at baseline and follow-up. Efficacy and safety of semaglutide were evaluated in participants across 3 baseline frailty strata. Effects of semaglutide on frailty burden were also assessed.
Results: Of the 1,145 participants, 110 (9.6%) were nonfrail, 343 (30.0%) were more frail, and 692 (60.4%) were most frail. Semaglutide-mediated weight loss was similar across frailty strata (Pinteraction = 0.38). However, the effects of semaglutide on KCCQ-CSS varied by frailty status; participants who were most frail had the greatest improvement at 52 weeks (nonfrail mean difference: -1.5 [95% CI: -8.4 to 5.4]; more frail mean difference: 3.7 [95% CI: -0.2 to 7.6]; most frail mean difference: 11.0 [95% CI: 8.1-13.8]; Pinteraction < 0.001). Semaglutide reduced the burden of frailty during follow-up (OR for being nonfrail at 52 weeks: 3.16 [95% CI: 2.44-4.09]; P < 0.0001).
Conclusions: Semaglutide resulted in a similar reduction in BW across frailty subgroups but greater improvements in HF-related symptoms. Moreover, semaglutide reduced frailty burden after 52 weeks of treatment. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511) (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470).
Keywords: frailty; glucagon-like peptide-1 receptor agonist; heart failure with preserved ejection fraction; obesity; weight loss.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Funding Support and Author Disclosures This trial was funded by Novo Nordisk A/S, Søborg, Denmark. Administrative support for manuscript development was funded by Novo Nordisk A/S. Dr Pandey has received research support from the National Institutes of Health (NIH), American Heart Association, Ultromics, Roche, Applied Therapeutics, and Gilead Sciences; has received honoraria outside of the present study as an advisor or consultant for Tricog Health, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Axon Therapies, Medtronic, Edwards Lifesciences, Science 37, Novo Nordisk, Bayer, Merck Sharp and Dohme, Semler Scientific, Sarfez Pharmaceuticals, and Emmi Solutions; has received nonfinancial support from Pfizer and Merck Sharp and Dohme; and is a consultant for Palomarin, with stock compensation. Dr Kitzman has received partial support from the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and NIH grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, U24AG059624, and U01HL160272; and has received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has held stock ownership in Gilead Sciences. Dr Borlaug has received research support from NIH grants R01HL128526, R01HL162828, and U01HL160226, the United States Department of Defense grant W81XWH2210245, and research grant funding from AstraZeneca, Axon Therapies, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck Sharp and Dohme, NGM, Novo Nordisk, NXT, and VADovations; and has been named inventor (U.S. patent No. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Butler has served as a consultant to Abbott, American Regent, Amgen, Applied Therapeutics, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, CardioCell, Cardior, CSL Behring, CVRx, Cytokinetics, Daxor, Edwards Lifesciences, Element Science, Faraday, Foundry, G3P, Imbria, Impulse Dynamics, Innolife, Inventiva, Ionis, Levator, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck Sharp and Dohme, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, PharmaIN, Prolaio, Pulnovo, Regeneron, Renibus, Roche, Salamandra, Salubris, Sanofi, scPharmaceuticals, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr Davies has acted as consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; has served as an advisory board member for AstraZeneca, Carmot/Roche, Medtronic, Pfizer, and Zealand Pharma; has served as a speaker for Amgen and AstraZeneca; and has received grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi-Aventis. Dr Shah has received research grants from AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck Sharp and Dohme, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Verma has received speaker honoraria and/or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical, Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck Sharp and Dohme, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. Dr Rönnbäck is an employee and shareholder of Novo Nordisk. Dr Domdey is an employee and shareholder of Novo Nordisk. Ms Liisberg is an employee and shareholder of Novo Nordisk. Dr Shou has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Perna has received honoraria from Novo Nordisk. Dr Ahmed has served as a consultant or on an advisory board for AstraZeneca, Abbott, Medtronic, Novo Nordisk, Pfizer, and Pharmacosmos. Dr Fu has received honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka; and has served as an advisor to US2.ai. Dr Petrie has received support from the British Heart Foundation Centre of Research Excellence Award (RE/13/5/30177 and RE/18/6/34217+); has received research funding from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; and has served as a consultant and on trial committees for Abbott, Akero, Applied Therapeutics, Amgen, AnaCardio, Biosensors, Boehringer Ingelheim, Corteria, Novartis, AstraZeneca, Novo Nordisk, AbbVie, Bayer, Horizon Therapeutics, Foundry, Takeda, Cardiorentis, Pharmacosmos, Siemens, Eli Lilly, Vifor, New Amsterdam, Moderna, Teikoku, LIB Therapeutics, 3R Lifesciences, Reprieve, FIRE 1, Corvia, and Regeneron. Dr Kosiborod has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck Sharp and Dohme (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca and Boehringer Ingelheim; has held stock in Artera Health and Saghmos Therapeutics; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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